Prion diseases are uncommon fatal neurodegenerative disorders which have gained scientific and public importance as a result of major advances in the understanding of the nature of the causative agent, and the emergence of new forms of these diseases in both animals and man. The transmissible agent in prion diseases is unique and is closely associated with an abnormal isoform of a widely distributed cell-surface glycoprotein, prion protein. The precise mechanisms of conversion to the abnormal isoform are unknown; changes in protein folding are of major importance. The abnormal isoform of the protein accumulates in the central nervous system in all prion diseases, but the processes involved in protein accumulation and the pathogenesis of neuronal dysfunction and cell death are poorly understood. Human prion diseases occur as sporadic, familial, and acquired disorders, the most recently identified of which is new variant Creutzfeldt-Jakob disease, which has been aetiologically linked to exposure to the bovine spongiform encephalopathy agent through the food chain. Surveillance of human prion diseases will be crucial in the assessment of the impact of this new disease in the United Kingdom and elsewhere. Effective surveillance depends on accurate diagnosis, which in turn places a high priority on autopsy in suspected cases; neuropathology is essential for the diagnosis of human prion diseases. Phenotypic variation is prominent in all forms of human prion disease; future classifications of these disorders are likely to incorporate genetic and biochemical data in addition to clinical and pathological parameters.